There is considerable public and professional concern that the two most widely prescribed stimulants for youth with attention-deficit/hyperactivity disorder (ADHD), mixed salts of amphetamine (MAS) and methylphenidate (MPH), may increase the risk of stroke, myocardial infarction, and other vascular events. These safety concerns are based on spontaneous adverse event reports of vascular disease developing in patients receiving MAS and MPH and the known pressor and chronotropic effects of these stimulants. Yet because large population-based studies have not previously compared the rate of vascular events among youth who do and do not receive these stimulants, no one knows whether, to what extent, and under what conditions MAS and MPH increase the risk of vascular events in young people. This study will examine associations between stimulant treatment and risk of myocardial infarction, stroke, transient cerebral ischemia, angina, and arrhythmia in youth, ages 6 to 21 years, treated for ADHD. Our primary aims are to: 1) evaluate whether stimulant treatment of ADHD increases the risk of vascular events;2) determine whether MAS is associated with a greater risk of vascular events than MPH and whether the risk of vascular events is more strongly related to longer as opposed to shorter duration of stimulant treatment;3) examine whether patient age, gender, comorbid medical diseases and co-prescribed medications that predispose to vascular disease moderate the effects of MPH and MAS on the risk of vascular events;and 4) assess whether risk of vascular events increases shortly after stimulant initiation or dosage increase. We will use Cox proportional hazards models and case crossover analyses with time dependent measures of stimulant treatment to assess these associations. Eleven years of integrated prescription and claims data from a large privately insured patient population will be used to determine whether and under what clinical circumstances MPH and MAS increase the risk of vascular events in young people. Data will be extracted concerning the pattern of stimulant treatment and incidence of vascular events of over 350,000 youth treated for ADHD. The size and scope of this data provide a rare opportunity to evaluate effects of stimulants on risk of vascular events. The results will directly inform future practice-based research as well as clinical and regulatory efforts to improve the safety of stimulant treatment in the community management of children with ADHD. PUBLIC HEALTH RELEVANCE: Despite concern that the most commonly prescribed stimulants may increase the risk of stroke, heart attacks, and other serious vascular events, no one knows whether, to what extent, and under what conditions stimulants actually increase these risks. This population-based study will determine whether stimulant treatment increases the risk of serious vascular events in youth with attention-deficit/hyperactivity disorder (ADHD) and will identify youth at especially high risk. The results will directly inform efforts to improve the safety of stimulant treatment in the community management of ADHD.